This invention relates to a method of inhibiting the production of interleukin-1 by monocytes and/or macrophages in a human in need thereof which comprises administering to such human an effective, interleukin-1 production inhibiting amount of a diaryl-substituted imidazole fused to a second heterocyclic ring containing a nitrogen bridgehead atom wherein said second ring may also contain sulfur, oxygen or an additional nitrogen atom, and may contain additional unsaturation.
This invention relates to a method of inhibiting the production of Tumor Necrosis Factor (TNF) by monocytes or macrophages in a mammal in need thereof which comprises administering to such mammal an effective, TNF production inhibiting amount of a compound of Formula (II) as described herein. The compounds of Formula (II) are generally described as diaryl-substituted imidazole fused to a second heterocyclic ring containing a nitrogen bridgehead wherein said ring may also contain sulfur, oxygen, or an additional nitrogen atom, and may contain additional unsaturation.
Lednicer, U.S. Pat. No. 3,455,924, issued Jul. 15, 1969, describes compounds of the formula: ##STR1## wherein Z is a bivalent radical selected from the group consisting of: ##STR2## in which up to two of the parameters R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of hydrogen, lower alkyl and lower alkoxy having 1 to 4 carbon atoms, inclusive, hydroxy and nitro and the remaining parameters are hydrogen.
Adams et al., U.S. patent application Ser. No. 07/255,816, filed Oct. 11, 1988, generically discloses pyridyl substituted pyrrolo-[2,1-a]-imidazoles and pyridines as useful for inhibiting the 5-lipoxygenase pathway of arachadonic acid metabolism in an animal in need thereof. Specifically disclosed are the following compounds:
2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a]-imida zole; PA0 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7,-dihydro-[5H]-pyrrolo[1,2-a]im idazole; PA0 2-(4-ethylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazol e; PA0 2-(4-ethylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imid azole; PA0 2-(4-methylthiophenyl)-3-(4-(2-methyl)pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2 -a]imidazole; PA0 2-(4-methylsulfinylphenyl)-3-(4-(2-methyl)pyridyl)-6,7-dihydro-[5H]-pyrrolo [1,2-a]imidazole; PA0 6-(4-methylthiophenyl)-5-(4-pyridyl)-2,3-dihydro-imidazo[2,1 -b]thiazole; PA0 5-(4-methylthiophenyl)-6-(4-pyridyl)-2,3-dihydro-imidazo[2,1-b]thiazole; and PA0 3-(4-methylthiophenyl)-2-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazo le. PA0 2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazo le; PA0 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imi dazole; PA0 2-(4-ethylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazol e; PA0 2-(4-ethylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imid azole; PA0 2-(4-methylthiophenyl)-3-(4-(2-methyl)pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2 -a]imidazole; PA0 2-(4-methylsulfinyiphenyl)-3-(4-(2-methyl)pyridyl)-6,7-dihydro-[5H]-pyrrolo [1,2-a]imidazole; PA0 2-(4-methoxyphenyl)-3-(4-pyridyl)-imidazo[1,2-a]-pyridine; PA0 5-(3,4-(methylenedioxy)phenyl)-6-(4-pyridyl)-2,3-dihydroimidazo 2,1-b]thiazole; PA0 2-(4-methoxyphenyl)-3-(4-(2-methyl)pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a ]imidazole; PA0 2-(4-acetoxymethylthiophenyl)-3-(4-(2-methyl)pyridyl)-6,7-dihydro[5H]-pyrro lo[1,2-a]imidazole. PA0 2-(trimethylacetylthiophenyl)-3-(4-pyridyl)-6,7 -dihydro- [5H]-pyrrolo[1,2-a]imidazole; PA0 6-(4-methylthiophenyl)-5-(4-pyridyl)-2,3-dihydro-imidazo[2,1-b]-thiazole; PA0 5-(4-methylthiophenyl)-6-(4-pyridyl)-2,3-dihydro-imidazo[2,1-b]-hiazole; PA0 3-(4-methylthiophenyl)-2-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazo le; PA0 2-(4-propylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-al-imidaz ole; PA0 2-(4-methylthiophenyl)-3-(4-(2-ethyl)pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2 -a]-imidazole; PA0 2-(4-Mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]-imidazol e disulfide; PA0 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H]-pyrrolo[1,2-a]-imi dazole; PA0 5,6-dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[1,2-a]-imidazol e-7-ol; and PA0 5,6-dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[1, 2-a]-imidazole. PA0 2-Phenyl-3-pyridyl-6,7-dihydro-[5H]-pyrrolo-[1,2-a]-imidazole; PA0 2-4-Bromophenyl-3-pyridyl-6,7-dihydro- [5H]-pyrrolo-[1,2-a]-imidazole; PA0 2-(4-Methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a]-imida zole; PA0 2-(4-Fluorophenyl)- 3- (4-pyridyl)-6,7 -dihydro-[5H]-pyrrolo- [1,2-a]-imidazole; PA0 3-(4-Fluorophenyl)-2- (4- pyridyl) -6,7-dihydro- [5H]-pyrrolo- [1,2-a]-imidazole; PA0 2-(4-Pyridyl)-3-(4-methyl thiophenyl) -6,7-dihydro- [5H]-pyrrolo-[1,2-a]-imidazole; PA0 2-(4-Methylthiophenyl)-3-[4-(2-methylpyridyl)]-6,7-dihydro-[5H]-pyrrolo[1,2 -a]-imidazole; PA0 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-7H-pyrrolo[1,2-a]imidaz ole; PA0 5,6-Dihydro-2-(4-methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[1,2-a]-imidazol e-7-ol; PA0 2-(4-Acetoxymethylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a] -imidazole; PA0 2-(4-Methoxyphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole; PA0 2-(4-Methylsulfoxyphenyl)-3-(4-pyridyl)-6,7-dihydro[5H]-pyrrolo[1,2]-imidaz ole; PA0 2-(4-Ethylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a]-imidaz ole; or PA0 2-(4-Ethylsulfonylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a]-im idazole. PA0 6-(4-Fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-[2, I-b]thiazole-1-oxide; PA0 6-(4-Fluorophenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole-1,1-diox ide; or PA0 5-(4-Fluorophenyl)-6-(4'-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Bender et al., U.S. Pat. No. 4,794,114, issued Dec. 27, 1988, disclose a method of inhibiting the production of IL-1 by monocytes and/or macrophages in a human in need thereof which comprises administering to such human an effective, interleukin-1 production inhibiting amount of a compound of the formula: ##STR3## wherein:
One of R.sup.1 and R.sup.2 must be 4-pyridyl and the other is selected from monosubstituted phenyl wherein said substituent is selected from halo or C.sub.1-4 alkoxy;
X is CH.sub.2, CH.sub.2 CH.sub.2 or S(O)n; and
n is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
Dinarello et al., Int. J. Immunopharmacology, 6(1), 43-50 (1984), suggest that a product of arachidonate lipoxygenase is important in the sequence of events underlying cell activation for the production of human interleukin-1.
Griswold et al., Inflammation, 11(2), 189-199 (1987), discuss the inhibitory effects of 5-(4-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo-(2,1 -b)thiazole and other dual inhibitors of arachidonic acid metabolism (i.e., inhibitors of 5-lipoxygenase and cyclooxygenase mediated arachidonate metabolism) on the edematous and cellular component of arachidonic acid-induced inflammation.
Lee et al., Int. J. Immunopharmac., 10(7), 835-843 (1988), discuss that [5-(4-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo(2,1-b)thiazole], which inhibits both 5-lipoxygenase and cyclooxygenase-mediated arachidonate metabolism, was shown to be a potent inhibitor of IL-1 production by bacterial lipopolysaccharide (LPS)-stimulated human monocytes, and that other cyclooxygenase and/or 5-lipoxygenase inhibitors of arachidonic acid metabolism tested, with the exception of nordihydroguaiaretic acid, were inactive in inhibiting monocyte IL-1 production suggesting that the inhibition of IL-1 production by 5-(4-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo-(2,1-b)thiazole may be dissociated from its inhibition of fatty acid oxygenases.
There remains a need for compounds which are useful in inhibiting the production of interleukin-1 (IL-1) by monocytes and/or macrophages in a human in need of such inhibition.
Studies have indicated that TNF is a glycoprotein and that its activity is associated with high molecular weight components. Mouse and rabbit TNF have been isolated, as has human TNF which sequence is taught in U.S. Pat. No. 4,879,226, issued Nov. 7, 1989. TNF is synthesized as a prohormone and subsequently cleaved at several sites to yield the mature hormone. While the active polypeptide itself has been evaluated for treatment of tumors due to its ealier reported antineoplastic activity, this administration has not been without may severe toxicities. Overproduction of TNF has further been implicated in the pathogenesis of endotoxin/septic shock, See e.g., Carswell et al., Proc. Natl. Acad. Sci. USA, 72, 3666-3670 (1975). Endotoxin is the lippolysaccharide component of the cell wall of gram-negative bacteria, and is a macrophage activator which induces the synthesis and secretion of cytokines and other biologically active molecules such as TNF. In sepsis, TNF production leads to hypotension, vascular endothelial permeability, and organ damage, i.e., some of the results of endotoxic shock. Adult Respiratory Distress Syndrome (ARDS) is frequently associated with sepsis and multiple organ failure which has led to the suggested role of TNF in the pathogenesis of ARDS. TNF is also the agent responsible for the weight loss (cachexia) found in chronic catabolic disease states, such as long term parasitic and viral infections and malignancies. This weight loss is a handicap to recovery and may even be fatal.
TNF also appears to play a role as an early product in the inflammatory response. See e.g., Old., Nature, 330, 602-03 (1987). It further appears that among the cytokines, while TNF production precedes and augments the function of IL-1 and other cytokines there is no clear data on how the relationship among these molecules contributes to inflammation-related disease states. TNF activates macrophages and enhances their cytotoxic potential in vitro. TNF has been shown to be chemotactic for monocytes, suggesting that the production of TNF at sites of injury may function to recruit additional macrophages and activate those macrophages already present.
Among the various mammalian conditions for which TNF is implicated in mediating or exacerbating rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acute immune deficiency syndrome (AIDS), keloid formation, scar tissue formation, Crohn's disease, uclerative colitis, or other inflammatory skin conditions such as pyresis.
The ability to control the adverse effects of TNF is furthered by the use of the compounds of this invention for humans who are in need of such use. There remains a need for compounds which are useful in inhibiting the production of tumor necrosis factor (TNF) by monocytes and/or macrophages in a human in need of such inhibition.